The propiomelanocortin (POMC) gene produces a complex precursor polypeptide that is post-translationally cleaved into a series of peptide hormones. In response to stress, one of these hormones, ACTH, induces the production of glucocorticoids in the adrenal gland, which in turn act to suppress POMC transcription in the pituitary in a classical feedback loop regulatory mechanism. This gene manifests two important regulatory features, negative regulation of gene expression by steroids, and tissue- specific gene expression. The overall goals of the project are to identify and characterize tissue-specific and positive transacting factors that regulate POMC promoter activity, and to investigate mechanisms by which glucocorticoids mediate transcriptional repression. In previous studies, an unusual transcription factor (designated PO-B) was discovered. This protein activates POMC expression via a high- affinity DNA-binding site that is located between the TATA box and the cap site for initiation of RNA synthesis, but is not directly responsible for tissue-specific expression. Elements present between -480 and -120 are involved in cell-specific transcription. Furthermore, there is cooperation between upstream elements and the glucocorticoid receptor binding site in receptor-dependent repression. The -480/-320 region is required for efficient repression by the receptor.